p28-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17933692  150 ENSSCAWGEFSAYpIHMELCEMCDQYCLHPTDQVQRRSHNRECLQqhEQAMELSFaiarskdKTCGICFDTIMEKAGREK 229
Cdd:PHA03096 127 DEDNCYKGKYCEY-LHGDICDICEKYLLHPTDIKQRYNEQKTCLS--YQLRLLLS-------KICGICLENIKAKYIIKK 196

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 17933692  230 RFGILPNCNHIFCLECIRTWRQakqfENKITRACPECRVCSDFVC-------------PSAFWMETKEEKDKLLNDY 293
Cdd:PHA03096 197 YYGILSEIKHEFNIFCIKIWMT----ESLYKETEPENRRLNTVIVfiekinedlknniPSRYWIDDKYDKNLLSFRY 269

zinc finger;

                           10        20
                   ....*....|....*....|....*
gi 17933692    298 GAKDCKYFKKGEgkCPFGNKCFYKH 322
Cdd:smart00356   3 KTELCKFFKRGY--CPRGDRCKFAH 25

p28-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17933692  150 ENSSCAWGEFSAYpIHMELCEMCDQYCLHPTDQVQRRSHNRECLQqhEQAMELSFaiarskdKTCGICFDTIMEKAGREK 229
Cdd:PHA03096 127 DEDNCYKGKYCEY-LHGDICDICEKYLLHPTDIKQRYNEQKTCLS--YQLRLLLS-------KICGICLENIKAKYIIKK 196

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 17933692  230 RFGILPNCNHIFCLECIRTWRQakqfENKITRACPECRVCSDFVC-------------PSAFWMETKEEKDKLLNDY 293
Cdd:PHA03096 197 YYGILSEIKHEFNIFCIKIWMT----ESLYKETEPENRRLNTVIVfiekinedlknniPSRYWIDDKYDKNLLSFRY 269

CCCH-type zinc finger; This short zinc binding domain has the pattern of three cysteines and one histidine to coordinate the zinc ion. This domain is found in a wide variety of proteins such as E3 ligases.

                          10        20
                  ....*....|....*....|..
gi 17933692    21 TICRYYVRGICRFGELCRFSHD 42
Cdd:pfam18044   1 RLCRYFQKGGCRYGDNCRFSHD 22

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 17933692    214 CGICFDTIMEKAgrekrfgILPNCNHIFCLECIRTWRQAKQFEnkitraCPEC 266
Cdd:smart00184   1 CPICLEEYLKDP-------VILPCGHTFCRSCIRKWLESGNNT------CPIC 40

RING-H2 zinc finger domain; There are 8 cysteine/ histidine residues which are proposed to be the conserved residues involved in zinc binding. The protein, of which this domain is the conserved region, participates in diverse functions relevant to chromosome metabolism and cell cycle control.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 17933692   213 TCGICFDTIMEKAGREKRFG------ILPNCNHIFCLECIRTWRQAKQfenkitrACPECR 267
Cdd:pfam12678   2 TCAICRNPFMEPCPECQAPGddecpvVWGECGHAFHLHCISRWLKTNN-------TCPLCR 55

RING finger, HC subclass, found in the makorin (MKRN) proteins; The MKRN protein subfamily includes ribonucleoproteins that are characterized by a variety of zinc-finger motifs, including typical arrays of one to four C3H1-type zinc fingers and a C3HC4-type RING-HC finger. Another motif rich in Cys and His residues (CH), with so far unknown function, is also generally present in MKRN proteins. MKRN proteins may have E3 ubiquitin ligase activity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 17933692 212 KTCGICFDTIMEKagrEKRFGILPNCNHIFCLECIRTWRQAKQFENKITRACPECR 267
Cdd:cd16521   1 IECGICMEVVLEK---ERRFGILSNCNHVFCLECIREWRSSKDFENSIVRSCPICR 53

RING finger, HC subclass, found in makorin-2 (MKRN2) and similar proteins; MKRN2, also known as makorin RING finger protein 2, RING finger protein 62 (RNF62), or HSPC070, is a putative ribonucleoprotein that acts as a neurogenesis inhibitor acting upstream of glycogen synthase kinase-3beta (GSK-3beta) in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. It also functions in promoting cell proliferation of primary CD34+ progenitor cells and K562 cells, indicating its possible involvement in normal and malignant hematopoiesis. Mammalian MKRN2 contains three N-terminal C3H1-type zinc fingers, a motif rich in Cys and His residues (CH), a C3HC4-type RING-HC finger, and another C3H1-type zinc finger at the C-terminus. The third C3H1-type zinc finger, the CH motif, as well as the RING zinc finger are necessary for its anti-neurogenic activity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17933692 211 DKTCGICFDTIMEKAG-REKRFGILPNCNHIFCLECIRTWRQAKQFENKITRACPECR 267
Cdd:cd16731   1 DKVCSICMEVVYEKASaSERRFGILSNCNHTYCLSCIRQWRCAKQFENPIIKSCPECR 58

N1R/p28-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 17933692  208 RSKDKTCGICFDTIMEKAGREKRFGILPNCNHIFCLECIRTWRQAKqfenkitRACPECRVCSDFVCPSAFW 279
Cdd:PHA02929 171 RSKDKECAICMEKVYDKEIKNMYFGILSNCNHVFCIECIDIWKKEK-------NTCPVCRTPFISVIKSRFF 235

RING finger, HC subclass, found in topoisomerase I-binding arginine/serine-rich protein (Topors) and similar proteins; Topors, also known as topoisomerase I-binding RING finger protein, tumor suppressor p53- binding protein 3, or p53-binding protein 3 (p53BP3), is a ubiquitously expressed nuclear E3 ubiquitin-protein ligase that can ligate both ubiquitin and small ubiquitin-like modifier (SUMO) to substrate proteins in the nucleus. It contains an N-terminal C3HC4-type RING-HC finger which ligates ubiquitin to its target proteins including DNA topoisomerase I, p53, NKX3.1, H2AX, and the AAV-2 Rep78/68 proteins. As a RING-dependent E3 ubiquitin ligase, Topors works with the E2 enzymes UbcH5a, UbcH5c, and UbcH6, but not with UbcH7, CDC34, or UbcH2b. Topors acts as a tumor suppressor in various malignancies. It regulates p53 modification, suggesting it may be responsible for astrocyte elevated gene-1 (AEG-1, also known as metadherin, or LYRIC) ubiquitin modification. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. It also functions as a negative regulator of the prostate tumor suppressor NKX3.1. Moreover, Topors is associated with promyelocytic leukemia nuclear bodies, and may be involved in the cellular response to camptothecin. It also plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress. Furthermore, Topors is a cilia-centrosomal protein associated with autosomal dominant retinal degeneration. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa (adRP).

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 17933692 211 DKTCGICFDTImekaGREKrfGILPNCNHIFCLECIRTWrqakqfeNKITRACPECR 267
Cdd:cd16574   1 DSSCPICLDRF----ENEK--AFLDGCFHAFCFTCILEW-------SKVKNECPLCK 44

RING finger, H2 subclass, found in synoviolin and similar proteins; Synoviolin, also known as synovial apoptosis inhibitor 1 (Syvn1), Hrd1, or Der3, is an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis and plays a role in homeostasis maintenance. It also targets tumor suppressor gene p53 for proteasomal degradation, suggesting crosstalk between ER associated degradation (ERAD) and p53 mediated apoptotic pathway under ER stress. Moreover, synoviolin controls body weight and mitochondrial biogenesis through negative regulation of the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1beta. It upregulates amyloid beta production by targeting a negative regulator of gamma-secretase, Retention in endoplasmic reticulum 1 (Rer1), for degradation. It is also involved in the degradation of endogenous immature nicastrin, and affects amyloid beta-protein generation. Moreover, synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of rheumatoid arthritis (RA). It functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of RA. It promotes inositol-requiring enzyme 1 (IRE1) ubiquitination and degradation in synovial fibroblasts with collagen-induced arthritis. Furthermore, the upregulation of synoviolin may represent a protective response against neurodegeneration in Parkinson's disease (PD). In addition, synoviolin is involved in liver fibrogenesis. Synoviolin contains a C3H2C2-type RING-H2 finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 17933692 211 DKTCGICFDTIMEKAGRekrfgiLPnCNHIFCLECIRTWRQAKQfenkitrACPECR 267
Cdd:cd16479   1 DNTCIICREEMTVGAKK------LP-CGHIFHLSCLRSWLQRQQ-------TCPTCR 43

RING finger, HC subclass, found in RING finger protein 213 (RNF213) and similar proteins; RNF213, also known as ALK lymphoma oligomerization partner on chromosome 17 or Moyamoya steno-occlusive disease-associated AAA+ and RING finger protein (mysterin), is an intracellular soluble protein that functions as an E3 ubiquitin-protein ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell. It plays a unique role in endothelial cells for proper gene expression in response to inflammatory signals from the environment. Mutations in RNF213 may be associated with Moyamoya disease (MMD), an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. It also acts as a nuclear marker for acanthomorph phylogeny. RNF213 contains two tandem enzymatically active AAA+ ATPase modules and a C3HC4-type RING-HC finger. It can form a huge ring-shaped oligomeric complex.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17933692 211 DKTCGICFDTImekagreKRFGILPnCNHIFCLECIRTWRQAKqfenkitRACPECRV 268
Cdd:cd16561   2 EQECSICLEDL-------NDPVKLP-CDHVFCEECIRQWLPGQ-------MSCPLCRT 44

Zinc finger domain; This is a zinc finger domain found in Zinc finger CCCH-type with G patch domain-containing proteins such as ZIP. Functional studies indicate that ZIP specifically targets EGFR and represses its transcription, and that the zinc finger and the coiled-coil domains are central to that process.

                          10
                  ....*....|....*....
gi 17933692    23 CRYYVRGICRFGELCRFSH 41
Cdd:pfam18345   1 CKFFLKGRCRYGDKCRFAH 19

zinc finger;

                           10        20
                   ....*....|....*....|....
gi 17933692     20 QTICRYYVRGICRFGELCRFSHDL 43
Cdd:smart00356   4 TELCKFFKRGYCPRGDRCKFAHPL 27

HC subclass of RING (RING-HC) finger and its variants; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers. Some have a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers can be found in a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle, and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enables efficient transfer of ubiquitin from E2 to the substrates.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 17933692 213 TCGICFDtimekagrEKRFGILPNCNHIFCLECIRTWRQAKQFEnkitraCPEC 266
Cdd:cd16449   2 ECPICLE--------RLKDPVLLPCGHVFCRECIRRLLESGSIK------CPIC 41

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17933692 213 TCGICFDTIMEKAgrekrfgILPnCNHIFCLECI-RTWRQAKQFENkitrACPECRVC 269
Cdd:cd16597   7 TCSICLELFKDPV-------TLP-CGHNFCGVCIeKTWDSQHGSEY----SCPQCRAT 52

RING finger, HC subclass, found in RING finger protein 170 (RNF170) and similar proteins; RNF170, also known as putative LAG1-interacting protein, is an endoplasmic reticulum (ER) membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate (IP3) receptors (ITPR1) via the endoplasmic-reticulum-associated protein degradation (ERAD) pathway. A point mutation (arginine to cysteine at position 199) in the RNF170 gene is linked with autosomal-dominant sensory ataxia (ADSA), a disease characterized by neurodegeneration in the posterior columns of the spinal cord. RNF170 contains a C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17933692 211 DKTCGICFdtimekagREKRFGILPNCNHIFCLECIRT-WRQAKQFEnkiTRACPECR 267
Cdd:cd16553   1 DMECPICL--------QDARFPVETNCGHLFCGPCIITyWRHGSWLG---AVSCPVCR 47

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 17933692 213 TCGICFdtimekaGREKRFGILPnCNHIFCLECIR-TWRQAkqfeNKITRACPECR 267
Cdd:cd16609   5 TCSICL-------GLYQDPVTLP-CQHSFCRACIEdHWRQK----DEGSFSCPECR 48

RING finger, HC subclass, found in Saccharomyces cerevisiae increased recombination centers protein 20 (IRC20) and similar proteins; IRC20 is an uncharacterized ATP-dependent helicase that is probably involved in a pathway contributing to genomic integrity. IRC20 contains a typical C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17933692 210 KDKTCGICFDTImekagrekRFGILPNCNHIFCLECIRTWRQAKQfenkitrACPECR 267
Cdd:cd23135   2 QKLSCSICFSEI--------RSGAILKCGHFFCLSCIASWLREKS-------TCPLCK 44

RING finger, HC subclass, found in Drosophila melanogaster Bre1 (dBre1) and similar proteins; dBre1 is the functional homolog of yeast Bre1, an E3 ubiquitin ligase required for the monoubiquitination of histone H2B and, indirectly, for H3K4 methylation. dBre1 acts as a nuclear component required for the expression of Notch target genes in Drosophila development. dBre1 contains a C3HC4-type RING-HC finger at its C-terminus.

                        10        20        30
                ....*....|....*....|....*....|....*....
gi 17933692 228 EKRFGILPNCNHIFCLECIRTWRQAKQfenkitRACPEC 266
Cdd:cd16705  23 KRKDAVLTKCFHVFCLDCLRTRYETRQ------RKCPKC 55

RING finger, HC subclass, found in RING finger protein RNF5, RNF185 and similar proteins; RNF5 and RNF185 are E3 ubiquitin-protein ligases that are anchored to the outer membrane of the endoplasmic reticulum (ER). RNF5 acts at early stages of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) biosynthesis, and functions as a target for therapeutic modalities to antagonize mutant CFTR proteins in CF patients carrying the F508del allele. RNF185 controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical endoplasmic reticulum-associated degradation (ERAD) model substrates. Moreover, both RNF5 and RNF185 play important roles in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) are also included in this family. They possess E3 ubiquitin-protein ligase activity and may play a role in the growth and development of Arabidopsis. All members of this family contain a C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 17933692 214 CGICFDTIMEKagrekrfgILPNCNHIFCLECIRTWRQAKqfenkitRACPECRVC 269
Cdd:cd16534   3 CNICLDTASDP--------VVTMCGHLFCWPCLYQWLETR-------PDRQTCPVC 43